Gene therapy for the treatment of disease is perhaps the most exciting promise of modern medical science. It is feasible that the simple inhibition of a single gene could potentially achieve therapeutic goals in certain medical settings. Such is the case in excessive hair growth, in which selectively inhibiting genes involved in hair cycling can lead to decreased hair growth, and improvement of the clinical phenotype. As an initial drug target, we selected the hairless (hr) gene, which is mutated in the hairless (hr/hr) mouse model. Our earlier biological and morphological studies have demonstrated that hairless expression is required for normal hair cycling. In the absence of hairless expression, either in mutant mice or human patients with complete hair loss, there is no further hair growth after the first cycle - the hair is shed, the hair follicle is destroyed, and the hair never grows. We reasoned, therefore, that if we could transiently inhibit hairless gene expression using ribozyme technology, (mimicking the hairless phenotype), we could permanently inhibit hair growth. In our Preliminary Studies, we tested the in vitro and in vivo efficacy of a simple preparation of topically applied ribozymes directed against the hairless (hr) gene, and showed evidence for targeted hair follicle disruption. Encouraged by our initial proof-of-concept results, in this Phase I STTR proposal, we will investigate more sophisticated methods for improving efficacy, focused on developing effective delivery strategies to the hair follicle, such as liposomes. We will test the hypothesis that topical application of anti-hairless ribozymes encapsulated in liposomes will result in the arrest of hair growth, and recapitulate the pathological changes and permanent hair loss observed in mutant hairless mice. Our goal is to determine the optimal liposome composition for efficient delivery of ribozymes into the hair follicle, and increase our initial success in recapitulating the hairless phenotype following long-term treatment in mice. It is our plan to apply for Phase II STTR funding for extended pre-clinical studies immediately upon successfu/completion of Phase I STTR funding, and eventually to extend these studies into human clinical trials.